1. Field of the Invention
This invention relates to a magic angle spinning (“MAS”) nuclear magnetic resonance (“NMR”) probe for the analysis of solids and semi-solids. In addition, the invention relates to a probe having two or more MAS systems within the homogeneous region of the magnetic field.
2. Description of Related Art
Solid-state NMR spectroscopy is a powerful technique for the analysis of solids and semi-solids. It is a non-destructive and non-invasive technique that can provide selective, quantitative, and structural information about the sample being analyzed.
Maximizing the utility and increasing sensitivity and sample throughput for the analysis of materials using solid-state NMR spectroscopy is of interest because for most solid samples less than one percent of the time in the magnetic field is spent on data acquisition. The rest of the time (greater than 99%) is spent waiting for the spin populations to return to their equilibrium value via spin-lattice relaxation (T1). However, the spin-spin relaxation time, T2, is usually several orders of magnitude shorter than T1. This means that the preparation and acquisition time in a Fourier Transform solid-state NMR experiment is typically tens of milliseconds. Before the sample can be pulsed again, the sample must relax for several seconds to several hours as the bulk magnetization returns to its equilibrium value. During this time, the sample must remain in a large static magnetic field, but is not required to be in a homogeneous magnetic field.
One example of compounds that have long T1 times is pharmaceutical compounds. New drug compounds often are poorly crystalline or even amorphous, have long relaxation times, and are present at low levels in a formulation. This creates a significant problem for analyzing these compounds using solid-state NMR spectroscopy, because analysis times can range from a few minutes to a few days depending upon the state of the sample (i.e., bulk drug or formulated product), relative sensitivity (i.e., choice and number of different nuclei in molecule), and relaxation parameters. For example, aspirin is a representative pharmaceutical solid, and has a T1 relaxation time of approximately 30 seconds at 300 MHz such that the pulse delay between acquisitions must be at least 90 seconds to avoid saturation. With salicylic acid, the delay between acquisitions exceeds one hour. Thus, to quantify a mixture of two forms of a compound can take a few hours (for a sample with short relaxation times) to a few days. To analyze a series of formulated products may take a month or more of spectrometer time. This leads to low throughput, high cost per sample analysis, and has relegated solid-state NMR spectroscopy in many cases to be a prohibitively expensive problem-solving technique compared to other analytical techniques such as powder X-ray diffraction, infrared and Raman spectroscopy, and Differential Scanning Calorimetry (“DSC”).
Also, throughput has been a significant problem in NMR spectroscopy, because the design of the NMR magnet generally allows the analysis of only one sample at a time. Autosamplers have increased throughput by minimizing the time spent changing samples and by allowing continuous use of the spectrometer, but have not increased the number of samples that could be run if samples were changed promptly.
Some researchers have used strategies for the acquisition of multiple signals from multiple probes that are packed within the homogeneous portion of the magnet to maximize the utilization of an expensive analytical tool.
Oldfield, et al., A Multiple-Probe Strategy for Ultra-High-Field Nuclear Magnetic Resonance Spectroscopy, J. Mag. Res., Series A 107, 255-257 (1994), recognized more than a decade ago that throughput was a significant issue on high-field NMR spectrometers. He designed a “three-probe” system which contained three different samples simultaneously located in the homogeneous part of the magnet. Oldfield also proposed that one could incorporate sample spinning in one of the probes. The resolution of this system was reported as about 1 ppm. Typically, a resolution of 0.1 ppm is desirable for analysis of typical crystalline organic solids such as pharmaceuticals. This concept was extended to solution NMR spectroscopy by Raftery and coworkers in U.S. Pat. No. 6,696,838. Raftery showed that up to four different non-spinning samples could be located simultaneously in the homogeneous part of the magnetic field. The more non-spinning samples, however, the smaller the sample volume must be for all samples to be located simultaneously in the homogeneous region of the magnetic field.
The present inventors recently attempted to increase sensitivity by utilizing the fact that solid-state NMR spectroscopy, the sample must remain in a large static magnetic field, but is not required to be in a homogeneous magnetic field. Thus, multiple MAS systems were shuttled through the bore of the magnet as described in Munson et al., U.S. Pat. No. 6,937,020, which is incorporated by reference. Despite this significant advance in the art, two concerns arose with this probe design arising from (1) the mechanical movement of the probe by a distance between 3 to 20 cm; and (2) the eddy currents generated in the aluminum body of the probe after movement. The mechanical movement of a conventional probe can take up to one second or longer. The down side of this approach is that to cycle through seven modules would take at least seven seconds, and probably longer. Many samples have shorter relaxation times than that, and therefore it would be advantageous to have a design with a shorter switching time. Second, the movement of the probe in the magnetic field creates eddy currents, which manifest themselves in a change in resonance frequency of the NMR sample. This problem can probably be overcome by modifying the probe to minimize the metallic moveable parts.